Dermal uses of trans-retinoids for the treatment of photoaging

ABSTRACT

The dermal use of non-irritating retinoids such as the esters and amides of 13-cis and 13-trans-retinoic acid for effecting the reduction and reversal of photoaging and skin cancer is disclosed.

CROSS REFERENCE TO A RELATED APPLICATION

This is a divisional of co-pending application Ser. No. 284,185, filedon Dec. 14, 1988, now U.S. Pat. No. 4,994,491, which is in turn aContinuation-in-Part of Applicants' co-pending application, Ser. No.067,536, filed Jun. 29, 1987, now U.S. Pat. No. 4,885,311.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to dermal uses of non-irritating retinoids andparticularly to dermal uses of the esters and amides of certainstereoisomers of retinoic acid.

2. Description of the Prior Art

Chronic sun exposure has been determined to create a number of skindisorders including skin cancer which is usually discernible by thepresence of lesions known as keratoses as well as photoaging (or"dermatoheliosis") of the skin which is characterized by wrinkling,sallowness, roughness and mottled pigmentation. In a recent articleentitled, "Topical Tretinoin Improves Photoaged Skin," JAMA 259, vol. 4,pgs. 527-532, Jan. 22/29, 1988, the authors Webb et al. report thatphotoaging of the skin of middle-aged and elderly Caucasians could beimproved within a 16-week period by daily topical application of a creamcontaining 0.1% tretinoin (all-trans-retinoic acid).

A side effect reported in the article which complicates theadministration of tretinoin, is that the therapy is irritating to theskin and induces dermatitis of several weeks duration in almost all ofthe subjects undergoing the tretinoin therapy. Redness, peeling,stinging, burning and dryness were consistently experienced by nearlyall subjects. Eleven of fifteen subjects experienced dermatitis severeenough to require the use of topical steroids to control the dermatitis.Three of fifteen withdrew from the tretinoin therapy due to the severityof the tretinoin-induced dermatitis. Also positive effects on thehistology of the epidermal and stratum corneum layers of the dorsalforearm skin were noted in the tretinoin treated areas. Because of theseside effects, recommendation for use of the therapy is inhibited and isnot used to full advantage. A method of dermal therapy that would retainthe effectiveness of tretinoin but which would be essentiallynon-irritating would provide a much needed solution to the treatment ofphotoaging. Further, non-irritating effective treatment of other skindisorders such as skin cancer would meet a long felt need in dermaltherapy.

SUMMARY OF THE INVENTION

The present invention is directed to a method for retarding andreversing the effects of skin cancer and photoaging without theinducement of dermatitis wherein there is applied topically to theepidermis of the skin a non-irritating retinoid comprised of the estersand amides of the 13-cis and 13-trans-stereoisomers of retinoic acid,the retinoids having the formulae: ##STR1## wherein R' is H or any ofthe lower alkyls ranging from C₁ to C₆ ;

wherein R" is --OR', or ##STR2## wherein R"' is the hydrocarbon backboneof fatty acids; wherein R"" is R' or the hydrocarbon backbone of fattyacids;

wherein R""' is the lower alkyls ranging from C₁ to C₆ ; and further,

where there are two or more R', R", R"', R"", or R""' groups attached tothe same carbon or nitrogen, each R', R", R"', R"", or R""' group may bethe same as or different from the other R', R", R"', R"", or R""' groupsattached to that carbon or nitrogen.

The esters and amides of 13-cis-retinoic acid and 13-trans-retinoic acidare known to the art. For example, U.S. Pat. No. 4,677,120, theteachings of which are incorporated herein by reference, discloses theuse of esters and amides of 13-cis-retinoic acid for the treatment ofacne. Illustrative compounds include

1-(13-cis-retinoyloxy)-2-propanone,

1-(13-cis-retinoyloxy)-3-decanoyloxy-2-propanone,

1,3-bis-(13-cis-retinoyloxy)-2-propanone,

2-(13-cis-retinoyloxy)-acetophenone,

13-cis-retinoyloxy methyl 2,2-dimethyl propanoate,

2-(13-cis-retinoyloxy)-n-methyl-acetamide,

1-(13-cis-retinoyloxy)-3-hydroxy-2-propanone,

1-(13-cis-retinoyloxy)-2,3-dioleoylpropanone, and

succinimdyl 13-cis-retinoate.

The esters and amides of 13-trans-retinoic acid are disclosed incopending patent application U.S. Ser. No. 067,536 filed Jun. 29, 1987and assigned to the assignee of the present application, the teachingsof which are also incorporated herein by reference. Illustrativecompounds include

1-(all-trans-retinoyloxy)-2-propanone and

2-(all-trans-retinoyloxy)-4'-methoxyacetophenone.

Although the esters and amides of 13-cis-retinoic acid and13-trans-retinoic acid are known to the art for the treatment of acneand similar dermatological disorders, the utility of these retinoidcompounds for the non-irritating treatment of skin cancer and photoaginghas not been observed previously.

In addition to the use of the esters and amides of the 13-cis or transstereoisomer of retinoic acid for the retardation and reversal ofphotoaging, the use of these compounds extends to non-irritatingtreatments involving the retardation and reversal of additionaldermatological and cosmetic conditions which are ameliorated bytretinoin such as the effacement of wrinkles, improvement in appearance,namely color and condition of the skin, spots caused from exposure tothe sun as well as other skin disorders such as the decrease orelimination of skin cancers and the retardation of melanoma growth andmetastasis.

For the treatment of conditions such as are enumerated above,therapeutic retinoid compositions of this invention in the form oflotions or creams are preferable. Such creams or lotions are appliedthinly to the involved areas of the skin in frequencies of once to twicedaily, the frequency selected being that which is most suitable to theuser.

Thus in practicing the treatment of skin disorders such as skin cancerand photoaging in accordance with the practice of the present invention,the esters and amides of 13-cis or trans retinoic acid are topicallyapplied to the skin site exhibiting skin cancer or photoaging in anysuitable pharmaceutically-acceptable vehicle, as for example, a liquidcarrier such as propylene glycol-ethanol. A preferred liquid compositionis a solution of a small amount of at least one of the compounds of theinvention in a combination of (A) from about 25% to about 75% by volumeof 95% ethanol and (B) from about 75% to about 25% by volume of a liquidglycol. A small but effective amount of an antioxidant such as butylatedhydroxytoluene may also be included in the composition. A typicalsolvent carrier of this type comprises 70% by volume 95% ethyl alcoholand 30% by volume propylene glycol. An antioxidant at a concentration of0.01 to about 0.1% by weight may be incorporated in the carrier. Thepreferred concentration of the active compound in these compositions isat least about 0.01% by weight, more preferably from about 0.01% toabout 0.5% by weight and most preferably from about 0.05% to about 0.2%by weight, but any therapeutically effective concentration may be used.This method of use is similar to the method taught in U.S. Pat. No.4,677,120 of Parish, et al., the teachings of which are incorporatedherein by reference.

The practice of the present invention is illustrated by the followingexamples:

EXAMPLE I Topical Assay

The usefulness of the retinoid compounds of the present invention forthe inhibition of skin cancers was demonstrated by testing in theornithine decarboxylase (ODC) assay an ester of tretinoin represented bythe formula ##STR3## wherein R is --CH₂ COCH₃ (Compound I,1-(all-trans-retinoyloxy)-2-propanone) and an ester of isotretinoinrepresented by the formula ##STR4## wherein R is ##STR5## (Compound II,2-(13-cis-retinoyloxy)-4'-methoxyacetophenone).

The ODC/Retinoid Bioassay is based on the method of Verma, A. K. andBoutwell, R. K., Cancer Res. (1977) 37:2196-2201. The ODC assay measuresa compound's effect on the prevention of the induction of ODC, namelythe effect of the retinoid compound on the inhibition of the tumorpromoter 12-0-tetradecanoylphorbol-13-acetate (TPA) induced ODCactivity. The assay was carried out using CD-1 mice (aged 7 to 9 weeks).The dorsal hair of the mice was shaved 3-4 days before testing. Fourmice were used for each point. The test retinoids, at one of two doselevels (1.7 and 17 nmoles) dissolved in 0.2 ml of acetone was appliedtopically to the back of each shaved mouse. A single dose of TPA (17 nM)was applied to the back of each treated mouse 30 minutes later. Controlgroups were treated with either acetone alone, TPA, or tretinoin. Themice were killed by cervical dislocation 5 hours after TPA treatment.

The dorsal skin encompassing the shaved and TPA exposed area was excisedand placed in a 100 ml beaker containing distilled water maintained at51°-57° C. The skin was soaked for 50-70 seconds at this temperaturewith intermittent stirring. The skin was placed epidermis side up in achilled (0°-5° C.) stainless steel plate and the epidermal layer wasscraped off with a razor blade. The epidermal layers from the 4 micewere pooled and placed in a homogenization tube with 2 ml of ODA buffer(10 nM tris-HCl with 0.050 nM pyridoxal phosphate, 0.050 nMethylenediaminetetraacetic acid (EDTA), 1 mM dithiothreitol, pH 7.5).The pooled epidermal layers were homogenized for 15 seconds at 0° C.using a Polytron homogenizer at a setting of 7.5 The homogenate wascentrifuged at 30,000×g and the supernatant fraction was pipetted into astorage tube and frozen for about 72 hours.

The homogenate was assayed for ODC activity as described by Verma andBoutwell to measure the release of 14C--CO₂ from labelled DL(1--14C)ornithine. Incubations were carried out in disposable centrifuge tubeswith center well holders containing filter paper impregnated with sodiumhydroxide to absorb 14C--CO₂. The incubation mixture consisted of 90 μlof L-ornithine, 350 μl of ODC buffer, 100 μl of 14C-ornithine (1.32 nm,Sp. Act:4.4 pCi/pM) and 10 μl of test sample. After incubation at 37° C.for 45 minutes, 0.5 ml of 2M chilled citric acid (4° C.) was added andincubation was continued for an additional 30 minutes to insure completeabsorption of 14C--CO₂. The filter paper was removed from the centerwell holders and set in 1 ml of water in capped scintillation vials forat least 1 hour before adding RBI 3820 scintillation cocktail.Radioactivity was measured in a Tri Carb Scintillation Counter. Resultswere expressed as pmol of 14C-CO₂ released in 30 minutes per milligramof protein based on the specific activity of DL-14C-ornithine. Theresults are expressed in the Table below as the % reduction in ODCactivity as compared to the control.

                  TABLE                                                           ______________________________________                                                             ODC Activity                                                      Concentration                                                                             (nM CO.sub.2 /30 min/mg Protein)                         Compound (nM)        % Reduction                                              ______________________________________                                        I        17          76                                                                  1.7       74                                                       II       17          59                                                                  1.7        0                                                       Acetone    0.0        NA*                                                     TPA      17           0                                                       Tretinoin                                                                              17          87                                                       ______________________________________                                         *NA = not available                                                      

The results recorded in the Table indicate that the retinoid compoundsof the present invention possess biological activity that inhibits TPAinduced ODC activity rendering these compounds useful for treatingmalignant skin disorders.

EXAMPLE II

Compound II of Example I(2-(13-cis-retinoyloxy)-4'-methoxy-acetophenone) was evaluated for itspotential to produce primary dermal irritation after a single topicalapplication to the skin tissue of rabbits.

Twelve healthy, young, adult, female New Zealand White rabbits(Orycetolagus cuniculus), were used in the study. The animals werepurchased from a registered commercial breeding laboratory. At the startof the study, the animals were in the weight range between 2.0 and 3.0kilograms, and were approximately 11 weeks of age. Animals selected forthe test were not subjected to any previous experimental procedures, andtheir skin was free from irritation, trauma and disease.

A dose of 0.5 ml of a test solution composed of 0.025 g of2-(13-cis-retinoyloxy)-4'-methoxyacetophenone in a liquid solutioncomposed of 75 ml of ethyl alcohol, 25 ml of propylene glycol 400, and0.025 g by weight of butylated hydroxytoluene was applied to one intactand one abraded skin site per animal. Six animals were treated in thismanner.

A control group of six animals was treated in an identical manner exceptthat 2-(13-cis-retinoyloxy)-4'-methoxyacetophenone was absent from thecontrol solution.

The application sites were prepared by clipping the skin of the trunkfree of hair approximately 24 hours before application of the dose. Oneapplication site on each animal was abraded by making minor incisionsthrough the stratum corneum, but not sufficient to disturb the derma(that is, not sufficiently deep to produce bleeding). The secondapplication site was intact skin.

The dose was applied to a small area (approximately 6 cm²) of skin andcovered with a gauze patch which was held in place with Vetrapbandaging. The patches were applied to one intact site and one abradedsite per animal. The test substance was kept in contact with the skinfor 24 hours. The skin was not rinsed following the 24 hour exposureperiod.

Animals were observed for signs of erythma and edema 24 and 72 hoursafter application of the test material. Observations were scoredaccording to the "Draize Scale for Scoring Skin Reactions" as in Draize,J. H., "Dermal Toxicity", Appraisal of the Safety of Chemicals in Foods,Drugs and Cosmetics--Dermal Toxicity, pp. 46-59, Association of Food andDrug Officials of the U.S., Topeka, Kansas, 1965. Observations at thedifferent scheduled times indicated that no signs of erythema or edemaformation were evident in any of the 12 test animals at any observationtime period. Animals were weighed at the beginning and at the end of theobservation period. All 12 animals exhibited a gain in body weight. Noovert signs of toxicity were evident during the course of the study.

EXAMPLE III

2-(13-cis-retinoyloxy)-4'-methoxyacetophenone was evaluated in a studyof its potential to produce dermal irritation. Comparisons were made oftretinoin, isotretinoin, 2-(13-cis-retinoyloxy)-4'-methoxyacetophenone,and the vehicle solution.

In the first test, four solutions were used. The control consisted ofvehicle solution, namely a solution of 60% by volume ethanol and 40% byvolume polyethylene glycol. The other three solutions were 0.025%solutions of tretinoin, isotretinoin, or2-(13-cis-retinoyloxy)-4'-methoxyacetophenone in 60% by volume ethanoland 40% by volume polyethylene glycol. Four patients painted twosaturated Q-tips-full of each of the four solutions on four differentareas of the inner forearm, twice daily for ten days. No irritantreactions occurred.

In the second test, four other solutions were used. The controlconsisted of vehicle solution, namely a solution of 90% by volumeethanol and 10% by volume polyethylene glycol. The other three solutionswere 0.075% solutions of tretinoin, isotretinoin, or2-(13-cis-retinoyloxy)-4'-methoxyacetophenone in 90% by volume ethanoland 10% by volume polyethylene glycol. Four patients painted twosaturated Q-tips-full of each of the four solutions on four differentareas of the inner forearm, twice daily for ten days. Only one subjectexperienced an irritant reaction. On day two, the tretinoin are beganreacting with redness and peeling. On day seven, the isotretinoin arebegan reacting with redness and peeling. By day nine, both areas werestill reacting--the tretinoin area more intensely than the isotretinoinarea. There was no reaction in either the2-(13-cis-retinoyloxy)-4'-methoxyacetophenone or the control areas.

In the third test, three solutions were used. The three solutions were0.075% solutions of tretinoin, isotretinoin, or2-(13-cis-retinoyloxy)-4'-methoxyacetophenone in 90% by volume ethanoland 10% by volume polyethylene glycol. Four patients painted twosaturated Q-tips-full of the2-(13-cis-retinoyloxy)-4'-methoxyacetophenone solution twice daily onone cheek of their faces. To the other cheek they applied two saturatedQ-tips-full of either tretinoin or isotretinoin.

The tests were carried out in double-blind fashion, that is, neither thesubjects nor the investigator knew the contents of the solutions duringthe study.

Clinical assessments were made daily of the subjects' cheeks. Allsubjects developed irritant reactions by the third or fourth day of thestudy. Cheeks of subjects painted with solutions containing2-(13-cis-retinoyloxy)-4'-methoxy-acetophenone were found to be slightlyirritated or not irritated at all during the six days the study wasconducted. By way of contrast, the cheeks of subjects painted withsolutions containing tretinoin or isotretinoin developed reactions whichwere so intense with redness and peeling that all subjects discontinuedapplication on or before the sixth day of the study.

EXAMPLE IV

Four subjects aged 49 to 73, three females and one male havingsignificant, easily observed, sun-damaged, wrinkled, "aged" skin of theface and forearms were subjects of a study to determine the effect oftopical application of 2-(13-cis-retinoyloxy)-4'-methoxyacetophenone inthe treatment of dermatoheliosis. The three females had moderatelysevere sun-damaged skin and wrinkles of the forearms, hands and face.The one male (aged 73) had extremely severe sun damage in these areas aswell as multiple actinic keratoses. The four subjects were provided withand applied to their entire faces (omitting the eyelids) and dorsalsurface of the right forearm, once daily for 12 to 16 weeks, 0.1%concentration of 2-(13-cis-retinoyloxy)-4'-methoxyacetophenone in ahydrophilic cream vehicle. The left forearm of each patient was treateddaily with a non-medicated moisturizer of the patients' choice.

All subjects were evaluated every 4 weeks through the study for redness,peeling, skin surface texture and wrinkling. Biopsies (using a 4 mmpunch) were taken from the dorsal surface of the right upper forearm atthe beginning of the study and again from the same area at the end ofthe study. The biopsies were stained with H & E, Alcian Blue andcollagen/elastic stains and compared by a qualified dematopathologist.

Facial assessment of the patients indicated that all showed animprovement in their dermatoheliosis. Two of the four patients showedvery significant improvement in facial smoothness, dryness and finewrinkling. Moderate improvement of these parameters were observed in theother two patients. The improvements began at about two months into thestudy and continued throughout the remainder of the study.

All the patients involved in the study were pleased by the improvedappearance of their skin and noted that they felt their facial skin wasfresher, clearer and prettier during the study.

Assessment of the forearms of the patients indicated that three showedimprovement in surface texture (smoothness), surface dryness and finewrinkling within two months after application of the cream containing2-(13-cis-retinoyloxy)-4'-methoxy-acetophenone had been initiated. Thisimprovement was maintained throughout the remainder of the study and wasreadily apparent when right and left forearms were compared. The onepatient who did not show improvement had only used sparing applicationof the cream containing 2-(13-cis-retinoyloxy)-4'-methoxyacetophenoneand had limited treatment to one small spot on the forearm.

No significant irritation was experienced by any patient. Very slightpinkness and a feeling of slight tightness in facial skin developed intwo patients after more liberal use of the cream was encouraged.

Comparison of the biopsies taken at the onset of the study with thosetaken after the treatment period indicated no significant differences inbefore treatment and after treatment biopsies.

While this test did not have a control, the results were compared withthe results obtained from a similar study conducted by Weiss et al. inwhich 0.1% concentration of retinoic acid in a hydrophilic cream vehicleor vehicle alone was applied to facial skin and dorsal forearm skin. Inthe Weiss study, it was observed that vehicle alone had no clinical orhistological effect but that retinoic acid cream, after 16 weeks of usehad some positive effects on the surface texture and wrinkling ofsundamaged facial skin, and on the histology of the epidermal andstratum corneum layers of dorsal forearm skin. Also noted in this studywas a moderately severe irritancy level from using retinoic acid cream.

EXAMPLE V

The preparation of the compounds of the present invention is illustratedby the preparation of compounds I and II of Example I.

SYNTHESIS OF COMPOUND I

1-(all-trans-retinoyloxy)-2-propanone ##STR6##

Into a 100 ml round bottom flask was added 1.0 g (0.0033 moles) oftretinoin (retinoic acid from Sigma Chemical Co., St. Louis, MO), 25 mlof anhydrous methanol, and 0.2 g (0.0035 moles) of KOH. The solution wasstirred at room temperature until the tretinoin dissolved. After thesolvent was removed under vacuum, 25 ml of acetonitrile was added andthe solution was again concentrated to a semisolid under vacuum.Chloroacetone, (2.0 g, 0.032 moles), 0.1 g 18-crown-6 (0.00038 mole),and 100 ml of acetonitrile were added. The solution was stirred for 24hours at room temperature with a magnetic stirrer. The sample wasconcentrated to about 5 ml and chromatographed on a neutral aluminumoxide (Aldrich #19,997-4) column (14×1.8 cm). The alumina wasdeactivated with 20 ml of water per 1.0 kg of alumina.

The sample was eluted stepwise with 100 ml of 20% dichloromethane inhexane, 100 ml of 50% dichloromethane in hexane, and finally with 250 mlof dichloromethane. The sample eluted quickly and the vast majority ofthe impurities remained on the column. Fractions of 25 ml were collectedand evaluated by thin layer chromatography (TLC) on silica gel (EMReagents #5775) developed with ethyl acetate:heptane (1:3). Thefractions containing the product were combined and concentrated to givean orange oil which solidified on cooling to give 0.55 g of solid.

Triturating the sample with 10 ml of cold 95% ethanol raised the meltingpoint to 93°-94° C.

TLC on silica gel (EM Reagents #5735) developed with 1:3 ethylacetate:heptane showed one spot, R_(f) =0.41. TLC on aluminum oxide (EMReagents #5581) developed with 1:3 ethyl acetate:heptane showed onespot, R_(f) =0.73.

The NMR (CDC₃) spectrum of Compound 1 taken with a Varian EM 360-Aspectrometer was identical to the spectrum of tretinoin except for twoadditional peaks and the lack of a carboxylic acid peak. The twoadditional peaks were at 4.5 ppm (singlet, 2 protons, --OCH₂ CO--) and2.1 ppm (singlet, 3 protons --COCH₃).

Elemental analysis for the compound gives a theoretical value for C₂₃H₃₂ O₃ of 77.49% C and 9.05% H; the found values were 77.52% C and 9.17%H.

SYNTHESIS OF COMPOUND II

2-(13-cis-retinoyloxy)-4'methoxyacetophenone ##STR7##

To a 100 ml round bottom flask was added 2.0 g (0.0066 moles)13-cis-retinoic acid, 1.37 g (0.0042) moles cesium carbonate, 1.49 g(0.010 moles) 2-chloro-4'-methoxyacetophenone (a lachrymator), and 15 mlof dry dimethylformamide. The reaction mixture was stirred for 18 hours.

After this time, the reaction mixture was poured into 100 ml of water.The solution was stirred for a few minutes and the product separated asa semisolid which was collected by filtration. The product wascrystallized from ethanol to give 2.3 g (78% yield) mp 126°-129° C. TLCshowed minor impurities. The sample was recrystallized from 80 ml of 95%ethanol and allowed to cool to give 1.6 g (54% yield) mp 132°-134° C.

TLC on Silica gel (EM Reagents #5735) developed with 1/3 ethylacetate/heptane showed one spot, but the R_(f) of Compound II wasidentical to the R_(f) 2-chloro-4'-methoxyacetophenone which is 0.77.The two can be separated on aluminum oxide (EM Reagents #5581) developedwith 1/2 ethylacetate/heptane. The R_(f) of Compound II was 0.69. TheR_(f) of the chloro compound is 0.63.

The NMR (CDC13) of Compound II was identical to the spectrum ofisotretinoin except for three additional peaks and the lack of acarboxylic acid peak. The additional peaks were at 3.72 ppm (singlet, 3protons, --OCH₃), 5.15 ppm (singlet, 2 protons, --OCH₂ CO--), and 6.60,6.75, 7.55 and 7.70 (quadruplet, 4 protons, aromatic ring). Elementalanalysis for the compound gave a theoretical value for C₂₉ H₃₆ O₄ of %C77.64, %H 8.90; the found values were %C 77.71, %H 8.14.

I claim:
 1. A method for retarding and reversing the effects ofphotoaging in a human subject requiring said treatment without theinducement of dermatitis which comprises topical application on a dermalsite of said human subject a pharmaceutical composition which comprisesan effective photoaging treatment amount of a non-irritating retinoidselected from the group consisting of esters and amides of 13-transretinoic acid, the retinoid having the formula ##STR8## wherein R is amember of the group consisting of ##STR9## wherein R' is a member of thegroup consisting of H and lower alkyls ranging from C₁ to C₆ ;wherein R"is a member of the group consisting of ##STR10## wherein R"' is thehydrocarbon backbone of fatty acids; wherein R"" is a member of thegroup consisting of R' and the hydrocarbon backbone of fatty acids;wherein R""' is the lower alkyls ranging from C₁ to C₆ ; and further,where there are two or more R', R", R"', R"", or R""' groups attached tothe same carbon or nitrogen, each R', R", R"', R"", or R""' group may bethe same as or different from the other R', R", R"', R"", or R""' groupsattached to said carbon or nitrogen; admixed with apharmaceutically-acceptable topical vehicle.
 2. The method of claim 1,wherein said retinoid compound comprises from about 0.01% to about 0.5%by weight of said composition.
 3. The method of claim 1, wherein saidretinoid compound comprises from about 0.05% to about 0.2% by weight ofsaid composition.
 4. The method of claim 1, wherein said vehicle ispropylene glycol-ethanol and an antioxidant.
 5. The method of claim 1,wherein said retinoid compound is 1-(all trans-retinoyloxy)-2-propanone.